Project Summary/Abstract Nearly half of the human genome is derived from transposable elements (TEs) -- mobile genetic elements that replicate and insert copies of themselves throughout the genome. Each individual has a unique signature of TE insertions comprised of inherited germline insertions and acquired somatic insertions. This signature is a major source of genetic variation both between individuals and within an individual. TEs have the potential to alter the transcriptome in a variety of ways, but the extent of intra-individual TE-derived transcriptional diversity is unknown. Detecting the transcriptional effects of somatic transposition has historically been challenging given the rarity of each insertion event on a per cell basis. New methods are finally enabling simultaneous interrogation of genome and transcriptome from a single cell, making it possible to detect both germline polymorphic and somatic transposition events and directly probe their consequences. This proposal will leverage single cell multi- omics technology to map somatic TE-derived transcriptional and functional diversity in the brain. Understanding the functional impact of somatic TE activity will ultimately contribute to our understanding of individual variation underlying complex disease processes. The training aspect of this project will support the applicant?s career goal to lead a translational research group that investigates the functional effects of somatic variation on human disease processes. Training in single-cell genomics is essential to probe the influence of rare somatic mutations in the brain. The proposal will build upon the applicant?s previous experience with experimental biology and molecular neuroscience while supporting critical training in bioinformatics and computational genomics.